Approximately 1.5 to 2 million individuals suffer a traumatic brain injury (TBI) each year in the United States and many (24-96%) exhibit agitation and aggression. Antipsychotic drugs (APDs) are commonly used to clinically manage these behavioral sequelae despite a paucity of research into their effect on subsequent recovery. Studies from our laboratory have shown that a short and consistent exposure paradigm (i.e., once daily administration for 19 days) of the APDs haloperidol (HAL) and risperidone (RISP) negatively impact motor and cognitive function after TBI in rats. These detrimental effects may be mediated, in part, by D2 receptor antagonism as parallel experiments using the D2 receptor agonist, bromocriptine, demonstrated enhanced functional recovery. Hence, we propose to empirically evaluate functional recovery after TBI using clinically relevant APDs with different pharmacological actions on the D2 receptor; specifically, HAL (a strong D2 antagonist), RISP (a moderate D2 antagonist) and aripiprazole (ARIP) a partial agonist for the D2 and 5-HT1A receptors. Overall, we hypothesize that ARIP (1) will not be detrimental to functional recovery (because of a lack of D2 receptor antagonist effects), and (2) will enhance recovery (due to D2 and/or 5-HT1A agonist activity). Three specific aims are proposed to test the overall hypothesis. Aim 1 will compare both the short- term (3 weeks) and long-term (3 and 6 months) effects of short-and-consistent exposure of ARIP to HAL and RISP on motor (beam-balance/walk and rotarod), cognitive (spatial learning/memory retention), histological (CA1/CA3 cell survival, cortical lesion volume), Western blot (D2/5-HT1A receptor expression), and TBARS (oxidative stress) outcome after controlled cortical impact (CCI) injury. Aim 2 will compare both the short-term and long-term effects of intermittent dosing (i.e., once every 2, 3, 4, or 5 days) of HAL, RISP, and ARIP on the same endpoints as Aim 1. The rationale for intermittent dosing is that during clinical rehabilitation, not all patients with agitation require daily APD intervention and thus receive prn (i.e., as needed) or intermittent doses. Aim 3 will evaluate the moderating effect of a rehabilitation-relevant environmental enrichment (EE) paradigm on the motor, cognitive, and histological, and oxidative effects of HAL, RISP, and ARIP, examining both short and consistent exposure and intermittent dosing. The EE paradigm mimics the cognitive, physical, and social environment of rehabilitation settings. These various aims are designed to duplicate real world rehabilitation practice in an animal model. Additionally, these aims will inform our understanding of the mechanisms of APDs mediating the deleterious (e.g., HAL and RISP) or potentially beneficial (e.g., ARIP) effects after TBI and could possibly facilitate the discovery o agents to (1) combat TBI- induced agitation and aggression without negatively impacting behavioral recovery, and (2) positively impact outcome by enhancing the recovery process. Furthermore, these studies will have an immediate impact on clinical care by providing clinicians critical information about the effects of APDs after TBI. PUBLIC HEALTH RELEVANCE: To control agitation and aggression, which is exhibited in 24-96% of the 1.5 to 2 million individuals subjected to traumatic brain injury each year in the United States, antipsychotic drugs are commonly provided despite a paucity of research into their effect on the subsequent recovery process. Previous studies from our laboratory have shown that a short and consistent exposure paradigm (i.e., once daily administration for 19 days) of the antipsychotic drugs haloperidol and risperidone negatively impact motor and cognitive function after TBI in rats, which may be mediated, in part, by D2 receptor antagonism as parallel experiments using the D2 receptor agonist, bromocriptine, demonstrated enhanced functional recovery. Hence, we propose to evaluate motor and cognitive recovery after TBI by comparing haloperidol (a strong D2 antagonist), risperidone (a moderate D2 antagonist) and aripiprazole (a partial agonist for the D2 and 5-HT1A receptors) to test our overall hypothesis that aripiprazole (1) will not be detrimental to functional recovery (because of a lack of D2 receptor antagonist effects), and (2) will enhance recovery (due to D2 and/or 5-HT1A agonist activity), which will have an immediate impact by providing clinicians critical information about the effects of antipsychotic drugs after TBI.